11-aminoaliphatic - 5,10 - methanodibenzo(a,d)(1,4)cycloheptadienes and the salts thereof



United States Patent 3,423,425 ll-AMINOALIPHATIC 5,10 METHANODIBENZO-[a,d][1,4]CYCLOHEPTADIENES AND THE SALTS THEREOF Max Wilhelm, Allschwil,Switzerland, assignor to Ciba Corporation, New York, N.Y., a corporationof Delaware No Drawing. Filed May 18, 1965, Ser. No. 456,828 Claimspriority, application Switzerland, June 19, 1964,

8,060/64 US. Cl. 260-326.14 Int. Cl. C07c 87/28; A61k 27/00 13 ClaimsABSTRACT OF THE DISCLOSURE The present invention relates to newcycloheptadienes. Especially it concerns 5,l0-methanodibenzo[a,d] [1,4]cycloheptadienes that contain in ll-position an aliphatic hydrocarbonradical substituted by an amino group as the only substituent, and theirsalts.

The new compounds may contain further substituents. For example,substituents may be present on the aromatic nuclei (positions 1-4 and6-9). Such substituents are above alli lower alkyl radicals, loweralkoxy groups, halogen atoms or trifluoromethyl groups.

The new compounds may also be substituted in S-position and/or12-position, for example, by hydrocarbon radicals, for example, alkylradicals.

Alkyl radicals are primarily lower alkyl radicals, such as methyl,ethyl, propyl, isopropyl or straight-chain or branched butyl, pentyl orhexyl radicals bound in any position.

The lower alkoxy groups are, in particular, methoxy, ethoxy,,propoxy orbutoxy groups, and the halogen atoms are fluorine, chlorine or bromine.

Thehydrocarbon radical in ll-position that is substituted by an aminogroup is, in particular, an aminoalkyl radical or an amino-alkylideneradical in which the amino group may be unsubstituted or substituted.

The substituents of the amino group are above all lower hydrocarbonradicals that may also be interrupted .by hetero-atoms, for example,oxygen, sulfur or nitrogen atoms and that may 'be bonded to the alkyl oralkylidene radical and/or substituted by free hydroxyl groups. As lowerhydrocarbon radicals there may be mentioned above all lower alkylradicals, for example, methyl, ethyl, propyl, isopropyl, straight chainor branched butyl, pentyl or hexyl or heptyl radicals bound in anyposition, unsubstituted or alkyl-substituted cycloalkal radicals, forexample, cyclopentyl, cyclohexyl, cycloheptyl radicals, or alkyleneradicals, especially alkylene radicals having 3 to 7 chain members, forexample, butylene(l,4), pentylene(1,5), l,5-dimethylpentylene(1,5),hexylene(l,6) .and hexylene (1,5) radical-s. Radicals of the kinddefined that are interrupted by hetero atoms are, for example, oxa-,azaor thia-alkylene radicals, especially such radicals having 3 to 7chain members, for example, 3-aza-, 3-oxa or 3,423,425 Patented Jan. 21,1969 3-thia-pentylene-( 1,5 3-aza-hexylene-( 1,6),1,5-dimethy1-3-aza-pentylene-(1,5), 3-methyl-3-aza-pentylene (1,5) or3-hydroxy-ethyl-3-aza-pentylene-( 1,5 radicals. Aminoalkyl or-alkylidene radicals in which a substituent of the amino group is bondedto the alkyl radical are, for example, N-alkyl-pyrrolidinyl-alkyl or-alkylidene radicals or N-alkylpiperidyl-alkyl or -alkylidene radicals.

The amino group is primarily a secondary or tertiary amino group, forexample, a methylamino, ethylamino or propylamino group or adi-lower-alkylamino group, for example, a dimethylamino, diethylarnino,dipropylamino or N-methyl- -ethylamino group, an N-lower-alkyl-N-cycloalkylamino group, for example, an N-methyl-N- cyclopentylor-cyclohexylamino group, a pyrrolidino, piperidino, morpholino,thiam-orpholino or piperazino group, for example, the pyrrolidino,piperidino, morpholino, piperazino, N methyl piperazino orN-(fl-hydroxyethyl)-piperazino group.

The alkyl or alkylidene radical carrying the amino group is, inparticular, a lower alkyl or alkylidene radical, for example, a methyl,ethyl, ethylidene, propyl, propylidene, butyl or butylidene radical.

The new compounds possess valuable pharmacological properties that canbe demonstrated by experiments on animals, for example, on the mouse,the cotton rat, the white-cared marmoset and the fish Betta splendens.For example, they have a central inhibitory action that is characterizedby antagonism towards psychomotory substances, for example, mescaline,and by inhibition of the transmission of spinal reflexes, and cantherefore be used as sedatives and tranquilizers. In particular, the newcompounds have a histaminolytic action, which is shown, for example, byexperiments on guinea pigs, and thus can be used as histaminolyticagents. However, they are also suitable as additives for animalfeedstufts, since they engender better utilization of food. Furthermore,the new compounds can also be used as starting materials or intermediateproducts in the manufacture of other valuable compounds.

Compounds that are specially valuable are those of the formula clear, R

represent N-lower alkyl-pyrrolidinyl-( 2) or N-loweralkylpiperidinyl-(2)-alkyl or -alkylidene radicals, for example, theN-methylpyrrolidinyl-(2)- or N-methylpiperidinyl- (2)-ethyl or-ethylidene radical.

ll ('y Dimethylaminopropyl) 5,10 methanodibenzo[a,d][l,4]cycloheptadiene is specially effective.

The new compounds are prepared by methods in themselves known.

For example, the procedure is to treat a 5,10-methanodibenzo[a,d][1,4]cycloheptadiene that contains in ll-position as only substituent analiphatic radical substituted by a reactive esterified hydroxyl group,with ammonia or a primary or secondary amine.

A reactive esterified hydroxyl group is, for example, a hydroxyl groupesterified with a strong organic or inorganic acid, for example, ahalogen atom, for example, chlorine or bromine, or an arylsulfonyloxygroup, for example, a para-toluenesulfonyloxy group.

The reaction is carried out in the usual manner.

Another method for preparing the new compounds consists in reducing in a5,10-methanodibenzo[a,d] [1,4] cycloheptadiene that contains inll-position as only substituent an aliphatic hydrocarbon radicalsubstituted by an amino group and having an oxo group attached to atleast one of the carbon atoms that is bonded to the nitrogen atom of thesaid amino group, the oxo group into the methylene group by treatmentwith lithium-aluminiumhydride.

A further method for the manufacture of the new compounds consists inreducing in a 5,10-methanodibenzo [a,d][1,4]cycloheptadiene thatcontains in ll-position as only substituent an aliphatic hydrocarbonradical substituted by a cyano group, the cyano group into theaminomethyl group. The reduction is carried out, e.g. by means ofnascent hydrogen, for example, zinc and mineral acids, or by means ofcatalytically activated hydrogen, for example, hydrogen in the presenceof hydrogenation catalysts, for example, palladium, nickel or platinumcatalysts, or with lithium aluminum hydride.

The new compounds may also be obtained when a 5,10-methanodibenzo[a,d][l,4] cycloheptadiene that contains in ll-position asonly substituent an aliphatic hydrocarbon radical substituted by ahydroxyimino or nitro group or an imino group that may be substituted,for example, by the substituents indicated for the amino group, isreduced. Reduction is carried out in the customary manner, inparticular, by means of catalytically activated hydrogen, for example,hydrogen in the presence of a hydrogenation catalyst, for example, aplatinum, nickel or palladium catalyst, for example, platinum oxide,Raney nickel or palladium carbon. However, the groups indicated may alsobe reduced with a metal or with a complex metal hydride. For example,hydroxyimino groups in particular, can be reduced with sodium in alcoholor sodium amalgam or stannous chloride and hydrochloric acid. Nitrogroups may be converted into an amino group, for example, by reductionwith iron and hydrochloric acid or with aluminum amalgam. Imino groups(Schitfs bases) may be reduced, for example, with lithium-aluminumhydride or above all with sodium boron hydride. The reductions arecarried out in the usual manner. A double bond that may be present inthe aliphatic radical may be hydrogenated at the same time, depending onthe method of working adopted, especially in the case of the catalyticreduction of the groups indicated.

Another method of manufacturing the new compounds consists in treating a5,10-methanodibenzo[a,d] [l,4]cycloheptadiene that contains inll-position a hydroxy group and an aliphatic hydrocarbon radicalsubstituted by an amino group joined at ll-position by a single bond, insuch a manner that water is split off with formation of a double bond.The reaction is advantageously carried out by treatment with a strongacid, for example, a mineral acid, for example, sulfuric acid or ahydrohalic acid such as hydrochloric acid or hydrobromic acid.

Further substituents that may be present in the end products may beintroduced by known methods into the compounds thus obtained. Forexample, in the case of compounds that contain an amino grpup haying atleast one hydrogen atom, a substituent may be introduced into the saidgroup. This can be done, for example, by reaction with a reactive esterof an appropriate alcohol or by reductive alkylation, that is to say, byreaction with an appropriate oxo compound and subsequent reduction.Suitable reactive esters are, in particular, those already indicated.The reducing agents used are primarily catalytically activated hydrogenor di-light metal hydrides, for example, sodium boron hydride.

Furthermore, in the case of compounds obtained that have double bonds inthe radical in ll-position, the said double bonds can be hydrogenated.For example, llarninoalkylidene compounds that are obtained can bereduced to the corresponding aminoalkyl compounds. Reduction is carriedout in the customary manner, preferably by treatment with hydrogen inthe presence of a hydrogenation catalyst, for example, a nickel,platinum or palladium catalyst.

In the case of compound obtained that are substituted at the amino groupby hydrogenolytically eliminable radicals, for example, aaarylalkyl orbenzyl radicals, the said radicals can be split off in the usual mannerby hydrogenolysis.

The end products are obtained in the free form or in the form of theirsalts, depending on the conditions under which the process is carriedout; the salts are also included in the invention. Salts that areobtained can be converted into the free bases in known manner, forexample, with alkalis or ion exchangers. Free bases that are obtainedcan be converted into salts by reaction with organic or inorganic acids,especially those that are suitable for the formation of therapeuticallyuseful salts. Such acids are, for example, hydrohalic acids, sulfuricacids, phosphoric acids, nitric acid, perchloric acid, aliphatic,alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, forexample, formic acid, acetic acid, propionic acid, succinic acid,glycollic acid, lactic acid, malic acid, tartaric acid, citric acid,ascorbic acid, maleic acid, hydroxymaleic acid and pyroracemic acid;phenylacetic acid, benzoic acid, paraaminobenzoic acid, anthranilicacid, para-hydroxybenzoic acid, salicylic acid, para-aminosalicylicacid, embonic acid, methanosulfonic acid, ethanesulfonic acid,hydroxyethanesulfonic acid, and ethylenesulfonic acid; halogenbenzenesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid andsulfanilic acid; methionine, tryptophan, lysine and arginine.

These or other salts of the new compounds, for example, the picrates,can also be used for purification of the bases obtained; the bases areconverted into salts, the salts are separated and the bases areliberated from the salts. In view of the close relationship between thefree compounds and the compounds in the form of their salts, whenever afree base is referred to in this context, a corresponding salt is alsointended, provided such is possible or apropriate under thecircumstances.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, or inwhich the starting materials are formed under the reaction conditions,or in which the reaction components may be used in the form of theirsalts.

Mainly those starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being specially valuable.

The 5,10 methanodibenzo[a,d] [l,4]cycloheptadienes, that contain ahydroxy group in ll-position and an aliphatic hydrocarbon radicalsubstituted by an amino group that is joined at ll-position by a singlebond, used as starting materials may be obtained, for example, bytreating an ll-oxo-S,l0-methanodibenzo[a,d] l,4]cycloheptadiene with anorganometallic compound of the formula in which A represents an aminogroup, Z represents an aliphatic hydrocarbon radical, and X represents ahalogen atom.

The 1l-oxo-S,IO-methanodibenzo[a,d] [1,4] cycloheptadienes required forthis purpose are new.

It has been found that these11-ox0-5,10-methanodibenzo[a,d][1,4]cycloheptadienes are obtained bysolvolysing an appropriate 9,10-dihydro-9,10-ethanoanthracene whichcontains a sulfonyloxy group in the ll-position and, if desired,hydrolysin g the resulting compounds and oxidizing the resulting1l-hydroxy-S,10-methanodibenzo[a,d] [1,4]cycloheptadienes to the ll-oxocompounds.

The sulfonyloxy groups are, in particular, hydroxyl groups esterifiedwith alkyl or arylsulfonic acids, for example, a benzene sulfonyloxygroup, a para-toluenesulfonyloxy group or a parabromobenzene-sulfonyloxygroup.

The ll-hydroxy compounds are obtained directly when the solvolysis iscarried out in water or in an aqueous solvent, for example, aqueousacetone, aqueous lower alkanols, for example, aqueous methanol orethanol. The reaction is advantageously carried out in a neutral orslightly basic medium and preferably at an elevated temperature. Whensolvolysis is carried out in anhydous solvolysing solvents, for example,lower alkane carboxylic acids such as formic acid or acetic acid, thecorresponding ll-lower alkanoyloxy compounds are obtained first whichare then hydrolysed in known manner to the ll-hydroxy compounds. Thereaction is advantageously carried out in the presence of a salt of thecarboxylic acid selected, for example, an alkali metal salt such as thesodium or potassium salt, and at an elevated temperature.

Oxidation of the ll-hydroxy group to form the ll-oxo group is carriedout by a method in itself known, for example, by the Oppenauer method orby treatment with one of the customary oxidizing agents, for example, acupric salt, manganese dioxide or, above all, with a compound ofhexavalent chromium, for example, sodium dichromate, or especiallychromium (VI) oxide. Oxidation is carried out as usual.

By virtue of their physical properties, mixtures of stereoisomers thatare obtained can be separated in the usual manner, for example, byfractional crystallization or absorption, elution and crystallization.

The remaining starting materials are known or, if they are new, may beprepared by methods in themselves known, for example, from thell-hydroxyor ll-oxo-S, methanodibenzo[a,d] [1,4]cycloheptadienesindicated above.

Compounds that contain one or more asymmetrical carbon atoms may be inthe form of racemate mixtures, pure racemates or optical antipodes.

Mixtures of racemates, by virtue of the physicochemical differencesbetween the components, can be resolved into the stereoisomeric pureracemates (diasteroisomers) in known manner, for example, bychromatography and/or fractional crystallization.

Racemic starting materials or end products can likewise be resolved intothe optical antipodes by known methods, for example, as follows: theracemic bases, dissolved in a suitable inert solvent, are reacted withan optically active acid, and the salts obtained are separated into thediastereoisomers (for example, by utilizing their different degree ofsolubility) from which the antipodes of the new bases can be liberatedby the action of an alkaline agent. Optically active acids that arewidely used are d-tartaric acid and l-tartaric acid, di-ortho-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid andquinic acid. Separation can also be carried out, for example, byrecrystallizing the pure racemate obtained from an optically activesolvent.

The new compounds can be used in the free form or in the form of theirsalts, for example, for the manufacture of pharmaceutical preparationscontaining the said compounds in admixture with organic or inorganic,solid or liquid pharmaceutical excipients suitable for enteral orparenteral administration. Suitable excipients are substances that donot react with the new compounds, for example, water, gelatine, lactose,sta rch, stearyl alcohol, magnesium stearate, talc, vegetable oils,benzyl alcohols, gums, propylene glycols, white petroleum jelly andother known medicinal excipients. The pharmaceutical preparations maybe, for example, tablets dragees or capsules, or in liquid form assolutions, suspensions or emulsions. They may be sterilized and/ orcontain adjuvants such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure or buffers. They may further contain other therapeuticallyvaluable substances. The pharmaceutical preparations are prepared byconventional methods.

The new compounds can also be used in the form of animal feedstutfs oradditives for animal feedst'utfs. The usual extenders, diluents, orfeedstuffs are used.

The following examples illustrate the invention.

EXAMPLE 1 12 grams of 1l-hydroxy-l1-(v-dimethylaminopropyD-5,10-methanodibenzo [a,d] [1,4]cycloheptadiene are heated for 3 hours atthe boil in 20 milliliters of concentrated hydrochloric acid and 60milliliters of glacial acetic acid. The reaction mixture is thenevaporated in vacuo at C. 50 milliliters of 2 N sodium hydroxidesolution are added to the residue and the batch is extracted withmethylene chloride. The organic layer is washed with water, dried andevaporated. The residue comprises 11- ('y-dimethylaminopropylidene) 5,10methanodibenzo- [a,d] [1,4]cycloheptadiene of the formula whosehydrochloride melts at 211 C.

The 1l-hydroxy-l1-( -dimethylaminopropyl) 5,10 methanodibenzo[a,d][1,4]cycloheptadiene used as starting material can be prepared in thefollowing manner:

grams of anhydrous sodium acetate are added to a solution of 500 gramsof 11- (para-toluenesulfonyloxy)- 9,10-dihydro-9,IO-ethanoanthracene(RM. to 163 C.; prepared by reacting 11-hydroxy-9,1'0-dihydro-9,10-ethano-anthracene with para-toluene sulfonyl chloride in pyridine) in2.5 liters of glacial acetic acid, and the whole is stirred for 5 hoursat 120 C. The acetic acid is subsequently distilled off in vacuo. 500milliliters of water and 500 mililiters of ether are added to theresidue, and the other layer is extracted several times with 2 N sodiumhydroxide solution. The batch is dried, the ether is evaporated, the oilthat remains is dissolved in 1.2 liters of methanol, 480 milliliters of2 N sodium hydroxide solution are added, and the batch is heated for 2hours at 70 C. The methanol is evaporated and the residue is extractedwith ether. The ether layer is washed with water, dried and evaporated.The residue comprises 11- hydroxy 5,10 methanodibenzo[a,d] [1,4]cycloheptadiene of the formula are added. The precipitate is disolved inmethylene chloride and extracted with 2 N sodium hydroxide solution.After drying and evaporation of the solvent, the substance that remainsis 1l-oxo-S,IO-methanodibenzo[a,d] [1,4] cycloheptadiene of the formulamelting at 113 to 115 C. after recrystallization from methanol.

1 milliliter of methyliodide is added to 6.3 grams of magnesium shavingsin 150 milliliters of absolute ether. As soon as the reaction commences,the batch is heated to the boil and 12 grams of 'y-dimethylaminopropylchloride in 150 milliliters of absolute ether are added dropwise. Whenthe chloride has been added, 1 milliliter of methyliodide is added andboiling is continued for a further 30 minutes. 17 grams of11-oxo-5,10-methanodi benzo[a,d][1,4]cycloheptadiene in 150 millilitersof absolute ether are then added dropwise, and boiling is continued for6 hours under reflux. After cooling the reaction mixture, 200milliliters of a ammonium chloride solution are added and the batch isextracted with 500 milliliters of methylene chloride. The organic layeris washed 'with Water, dried and evaporated. The crystalline residuecomprises 1l-hydroxy-ll('y-dimethylaminopropyl) 5,10 methanodibenzo[a,d][1,4]cycloheptadiene of the formula s err -m cs 2 melting at 118 to 120C. after recrystallization. The hydrochloride melts at 16 3 to 165 C.

The 1l-hydroxy-S,10-methano-dibenzo[a,d] 1,4]-cyclo heptadiene describedas interemdiate above may also be prepared in the following manner:

A solution of 10 grams of 1l-(para-toluenesulfonyloxy)-9,10-dihydro-9,IO-ethanoanthracene in 200 milliliters of alcohol and 50milliliters of 2 N sodium hydroxide solution is boiled for 2 hours underreflux. Subsequently, the solvent is evaporated in vacuo, the residue isdissolved in methylene chloride and extracted with water. 11- hydroxy-SIO-methanodib enzo [a,d][ 1,4] cycloheptadiene melting at 110 to 112 C.is obtained after drying and evaporation of the methylene chloride.After recrystallization from alcohol, the product melts at 113 C. and,according to its infra-red spectrum and mixed melting point, isidentical with the above described compound.

EXAMPLE 2 ca emcir whose hydrochloride melts at 167 C.

8 What is claimed is: 1. A member selected from the group consisting ofcompounds of the formula in which A stands for lower alkylenylidene, Rand R each stands for a member selected from the group consisting ofhydrogen, lower alkyl, cyclo-lower alkyl, lower alkyl-cyclo-lower alkyl,and, when taken together with the nitrogen atom, for a member selectedfrom the group consisting of pyrrolidino, piperidino, morpholino,piperazino, N-lower alkyl-piperazino or N-(B-hydroxyethyhpiperazino, Rand R each stands for a member selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy, halogen and trifluoromethyl, andacid addition salts thereof.

2. A member selected from the group consisting of compounds of theformula in which A stands for lower alkylene, R and R each stands for amember selected from the group consisting of hydrogen, lower alkyl,cyclo-lower alkyl, lower alkylcyclo-lower alkyl, and, when takentogether with the nitrogen atom, for a member selected from the groupconsisting of pyrrolidino, piperidino, morpholino, piperazino, N-loweralkyl-piperazino, N-lower alkyl-piperazino orN-(fi-hydroxyethyl)-piperazino, R and R each stands for a memberselected from the group consisting of hydrogen, lower alkyl, loweralkoxy, halogen and trifiuoromethyl, and acid addition salts thereof.

3. A member selected from the group consisting of compounds of theformula in which A stands for lower alkenylidene and R and R each standsfor lower alkyl.

5. A compound of the formula in which A stands for lower alkenylidene, Rfor hydrogen and R for lower alkyl.

6. A compound of the formula in which A stands for lower alkylene and Rand R each for lower alkyl.

7. A compound of the formula 9. An acid addition salt of a compoundclaimed in claim 5.

10. An acid addition salt of a compound claimed in claim 6.

11. An acid addition salt of a compound claimed in claim 7.

12. A member selected from the group consisting of 11(y-dimethylaminopropylidene)-5,IO-methanodibenzo-[a,d][l,4]cycloheptadiene and its acid addition salts.

13. A member selected from the group consisting of 11- ('ydimethylaminopr0py1)-5,l0-rnethanodibenzo[a,d] [1, 4]cycloheptadiene andits acid addition salts.

References Cited FOREIGN PATENTS 1,744 3/1963 France.

CHARLES B. PARKER, Primary Examiner. R. HINES, Assistant Examiner.

CASE 5&85/548 6/E 5 3 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3, 3n 5 Dated n ry 21, 1969 Inventm-(s) MaxWilhelm It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Column 8, lines 15-19, delete "when taken together with. piperazino,same column, lines 37- 41, delete "when taken together with..piperazino,

Signed and sealed this l th day of January I 972.

(SEAL) Attest:

EDWARDS M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer ActingCommissioner of Patents

